Resolved psoriasis lesions retain expression of a subset of disease-related genes

Abstract

Psoriasis is a complex inflammatory disease that usually heals without visible scarring. Histological evaluation often suggests complete resolution, but reversal of genomic disease-associated alterations has not yet been defined. Gene expression profiling was used to determine the extent to which the psoriasis genes were reversed after 3 months of etanercept treatment in patients who responded to treatment. We reviewed the histology, leukocyte counts, and PCR data for inflammatory genes, to compare recovery of these parameters and the genomic studies. Many cellular markers do return close to nonlesional levels, although five inflammatory genes did not improve by >75% (IL-12p35, MX1, IL-22, IL-17, and IFNγ). Psoriasis-related genes with <75% improvement were defined as comprising a "residual disease genomic profile," composed of 248 probe sets. Genes of interest in psoriasis tissue that did not return to baseline included LYVE-1, WNT5A, RAB31, and AQP9. It appears that even when the epidermal reaction in psoriasis is fully resolved, inflammation, as defined by expression of key cytokines and chemokines, is not completely resolved in treated lesions. We also found that structural cells of the skin continued to express molecular alterations, and that some subtle features of skin structure, for example, lymphatics, were not fully normalized with treatment.

Figure 1. Residual Disease Genomic Profile

a) Treatment response evaluated in the set of psoriasis genes (at fold change greater than 2 and a false discovery rate of 0.05). Genes that improved > 75% after 12 weeks of treatment were considered part of “molecular resolution” while those with < 75% form the “molecular remnant”. b) Example of treatment response of several genes. The x-axis refers to time during the clinical trial, with NL considered at 0, LS levels showing increase or decrease compared to NL levels, and genes that at week 12 attain this line have an improvement of 100%. Up-regulated psoriasis genes WNT5, TCRβ1 and RAB31 improved by < 75% (red lines), while AQP9 and LYVE1 were down-regulated that improved < 75% (green lines). STAT1, showed a complete remission of pathological expression (black line).

Figure 2. Immunohistochemistry for select genes in residual disease genomic profile

Representative staining in normal, NL, LS and after 12 weeks of etanecept treatment. a) LYVE-1 showed discernible lymphatic lumen in normal and NL skin compared to collapsed lymphatic vessels in LS skin and after 12 weeks of treatment. b) WNT5A showed increased expression in LS skin and even after 12 weeks of treatment compared to NL and normal skin. c) RAB31 identified many positive dermal cells in LS skin, which decreased after 12 weeks of treatment but did not completely return to NL levels. d) AQP9 showed decreased expression in LS skin compared to NL and normal skin and after 12 weeks of treatment. Bar= 100μm.